Gastric bypass in a pill
The hoopla about the new breakthrough drugs that can achieve weight loss almost as good as gastric bypass surgery have been acclaimed "bypass surgery in a pill." But do they work the same way? Yeah. Mostly. Probably.
But it must be admitted that we don't really know how any of these things cause remarkably big, durable and relatively pain free weight loss. Relatively pain free means compared to the hellish hunger from just not eating. The other amazing thing to my weak mind is that these new weight loss magic bullets are so easy and simple. They are not a hundred things. They are just one thing that you have to do. They kind of sound like all those stupid simple weight loss miracles that are advertised and sold all over.
Just to review gastric bypass briefly: Roux-en-Y gastric bypass surgery makes a small stomach and and skips ahead of a segment of the small intestine reconnecting the stomach down stream and leaving that skipped segment dangling but still connected so that digestive enzymes made by the pancreas can be delivered. Roux-en-Y gastric bypass causes the biggest weight loss of all - more than a quarter of your weight is lost on average. Gastric sleeve makes a small thin tube out of the stomach but leaves everything else connected normally. It delivers a little less than a quarter of pre-operative weight loss. Neither of these surgeries make you absorb less of the calories you eat nor do they make you eat less. Another mystery is why do they cause you to lose a big percentage of weight but then you stop losing. They just reset the set point.
The gastric-bypass-in-a-pill drugs act like two hormones called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), made by the small intestine. These 2 hormones together labelled the incretins do things like stimulate insulin secretion and regulate glucagon secretion. We think they cause weight loss by acting on you brain to decrease appetite. Semaglutide, a GLP-1 act-alike, will give you about 15% weight loss. And tirzepatide, that is a combined GLP-1 and GIP actor, causes about 20% weight loss on overage. Incidentally stimulating insulin secretion should make you fatter. Go figure. (more about these incretins see fat science https://johnditragliamd.substack.com/p/is-nausea-the-cure-for-obesity and https://johnditragliamd.substack.com/p/nausea-2-big-spider-in-the-ointment)
So does the surgery work by the action of the incretins? It's not entirely clear but the surgery does seem to increase these intestinal hormones. (1,2) Since the surgery causes more weight loss than incretins alone there must be other stuff the surgery does.
The first of those two recent study reports took 12 subjects who were obese but without type-2 diabetes and 12 otherwise similar subjects who had had Roux-en-Y gastric bypass (RYGB) and 12 more who had had sleeve gastrectomy (SG) more than a year before. They took these people and gave them a treatment that temporarily blocked the receptors on the pancreas for GLP-1 and GIP, first each separately and then both at the same time. Those receptors for GLP-1 and GIP cause the pancreas to secrete insulin when you eat and that insulin in turn causes you body to suck up the glucose out of the blood and into cells for fuel. When they measured the responses to meals by these blocker tricks they found that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB. So no pattern here.
But then some Norwegian neighbors of those Danish authors reported in the same month, December of 2022, that they did find a more straightforward increase of GLP-1 in obese customers who had sleeve gastrectomies and Roux-en-Y gastric bypass. So the GLP-1 blocking trick that the Danish investigators used that works by stimulating the pancreas to release insulin must not be the thing that causes weight loss.
The Norwegian investigators recruited patients with severe obesity scheduled for SG (15) and RYGB (14) and 15 matched controls. They were all fed a very low calorie diet during the 10 weeks of the study and everyone lost the same amount of weight. They found that the SG and RYGB operated patients both secreted way more GLP-1 in response to meals compared to the controls who were just dieting. Also between the 2 surgeries, secretion of GLP-1 was more than twice as high in the RYGB-ers than in the SG-ers. So maybe GLP-1 is really the secret sauce. Or about three quarters of the secret sauce since that's about the relative proportion of weight loss delivered between the GLP-1 mimetics vs Roux-en-Y gastric bypass. Fifteen percent weight loss vs 20%.
This increase in release of GLP-1 in response to meals by the obesity surgeries is thought to happen because the meal is dumped out quicker by the restricted stomach sizes of both procedures and in the case of RYGB further down stream in the intestines. This dumping causes those segments were GLP-1 is made to produce and secrete more of it.
This study also looked at other intestinal hormones that have been found to influence appetite and satiety.
Ghrelin is a hormone made by the stomach that increases when the stomach is empty and tells the brain that you're hungry. But the decrease in ghrelin was inconsistent and may have been influenced by the ketosis that all of the subjects experienced. Ketosis is a response to calorie restriction and also decreases ghrelin secretion and appetite.
Cholecystokinin and peptide YY are two other hormones made in the intestines in response to food and they both increase satiety but there were no significant differences in these hormone levels.
Interestingly there were not significant differences in hunger ratings between surgeries and controls but that may have been because all the patients had ketosis during the short term of the study which can block hunger to some extant. But ketogenic diets don't work in the long run for big sustained weight loss. Everyone knows that weight loss will ultimately make you ravenous unless you have bypass surgery or take semaglutide.
Still complicated.
1. Hindsø M et al. The importance of endogenously secreted GLP-1 and GIP for postprandial glucose tolerance and β-cell function after Roux-en-Y gastric bypass and sleeve gastrectomy surgery. Diabetes db220568 December 2022, DOI: https://doi.org/10.2337/db22-0568.
2. Aukan MI et al. Gastrointestinal hormones and appetite ratings after weight loss induced by diet or bariatric surgery.Obesity 19 December 2022 https://doi.org/10.1002/oby.23655